Perspective
Should antihistamines be re-considered as antiasthmatic drugs as adjuvants to anti-leukotrienes?

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Abstract

In spite of histamine mimicking the symptoms of allergic bronchoconstriction and severe anaphylaxis, histamine antagonists most probably represent no effective treatment for these conditions. Anti-leukotrienes proved effective for preventing attacks of allergic asthma. In vitro evidence supports a supra-additive effect of histamine H1 receptor antagonists and anti-leukotrienes in vitro, in asthma models utilizing human bronchi. The same seems to hold true for human allergen provocation tests in vivo. We conclude that combinations of second-generation antihistamines and anti-leukotrienes deserve a large-scale clinical trial for preventing and/or treating attacks of allergic asthma. If useful, these drugs could provide a cost-effective alternative to some recent antiasthmatics. Given that redundant mechanisms may be included in asthma pathophysiology, other combinations (including thromboxane or platelet activating factor antagonists) could also be considered.

Introduction

In the first half of the 20th Century there was great hope that antihistamines would suppress the symptoms of bronchial asthma and maybe other diseases involving bronchoconstriction or even anaphylaxis. Exogenous histamine induced bronchoconstriction, although with different potencies and efficacies in different animal species, humans showing an intermediate sensitivity. Histamine was detected in tissues and release of an “H-substance” − later that of histamine itself − was detected in the course of anaphylactic or other allergic reactions, from animal and human lungs (see Schild et al., 1951, Sheard et al., 1967, Sheard and Blair, 1970, Piper and Walker, 1973). Mast cells and basophils have been identified as the main source of the release of histamine, as well as other mediators of IgE-mediated reactions. These cell types (especially mast cells) are still considered as protagonists in allergic asthma, especially at its early phase. Considerable progress has been made concerning the way of mast cell activation in the course of antigen-fixed IgE reaction, the release of preformed and freshly-synthesized mediators, as well as other consequences of mast cell activation (for reviews see Holgate, 1999, Nauta et al., 2008, Rivera et al., 2008, Hamid and Tulic, 2009, Weller et al., 2011).

Section snippets

Histamine receptor antagonists

The hopes mentioned above were practically ruined by the very modest usefulness of antihistamines (histamine H1 receptor antagonists) in bronchial asthma, and also in anaphylactic shock; although these antagonists could inhibit the deleterious effects of injected (exogenous) histamine and are effective in milder forms of hypersensitivity reactions, such as hay fever and urticaria.1

Supra-additive relations between mediators

There are several examples of supra-additive interactions, “redundant mechanisms” of mediators (neurotransmitters, local hormones) in the mechanisms of physiological and/or pathopysiological reactions of the body. In such cases, antagonizing one of the mediators may yield no or only minor reduction in the reaction, but inhibiting additional mediators can result in profound inhibition of the process. Even simple addition offers some advantages, first of all, a reduction of dosage of the

Clinico-pharmacological studies with combined antihistamine−anti-leukotriene treatment

Promising human studies have been published with the combination of antihistamines and anti-leukotrienes. The studies were prospective provocation tests performed on a low number of asthmatics. Patients with allergic asthma were challenged with the allergen; bronchoconstriction was inhibited by zafirlukast or, to a lesser extent, by loratadine. Combining the two drugs yielded an approximately additive effect (Roquet et al., 1997). Similarly, a combination of azelastine and montelukast inhibited

Conclusions and the authors' thoughts about future perspectives

This minireview only deals with a special aspect of allergic asthma therapy, i.e., antihistamine–anti-leukotriene combination. Other types of asthma, e.g., exercise-induced bronchoconstriction, are beyond our current topic. We feel that there is ample evidence to justify larger-scale clinical studies with combinations of anti-leulotrienes (receptor antagonists or 5-lipoxygenase inhibitors) and second-generation H1 histamine receptor antagonists in patients with allergic asthma, as already

Acknowledgments

This study was supported by the Hungarian research grants ETT 03–372/2009 (Ministry of Welfare), Grants no. OTKA T-81984, and NK-78059 of Hungarian Research Funds and TÁMOP/ SROP-4.2.2/B-10/1–2010-0029. Experiments on human tissues have been approved by the Regional Research Ethics Committee and the National Research Council Ethics Committee (ETT-TUKEB). The technical contribution of Ms. Veronika Szombati and Mr. Norbert Kasza is gratefully acknowledged.

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